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Biochemical and Metabolic Limitations to Athletic Performance
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
These data support the assertion that the core-clock machinery partly regulates the gene transcriptional response to exercise—in other words, the genes turned on in response to, or off after cessation of, intense exercise and the magnitude partly regulated by an internal cellular “clock.” Additionally, genetic ablation of these molecular clocks such as Cry1 and Cry2 increased exercise capacity in mice and altered the exercise-induced gene signature (26), adding further weight to the evidence that the molecular clock may modulate the metabolic limits of exercise capacity. In human studies, cultured primary myotubes from endurance-trained athletes had preserved rhythmic gene expression of metabolic regulators SIRT1 and NAMPT, while myotubes derived from untrained individuals did not (20). These metabolic regulators (SIRT1 and NAMPT) are important indicators of metabolic capacity, as they are responsive to altered bioavailability of NAD+. As detailed earlier in this chapter, the ratio of NAD+/NADH is one crucial metabolic limit of prolonged muscular function, as they are crucial metabolites in generating ATP through oxidative phosphorylation. Indeed, NAD+/NADH is hypothesized (with some evidence) to fluctuate over the course of 24 hours (43) and may be one link between the molecular clock and exercise capacity. Specifically, altering the regulation of the molecular clock can modulate the bioavailability of NAD+ (43) and can also modify exercise performance and capacity (26).
Energy Metabolism, Metabolic Sensors, and Nutritional Interventions in Polycystic Kidney Disease
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Sonu Kashyap, Eduardo Nunes Chini
The use of nonspecific inhibitors, such as nicotinamide (NAM),45 and indirect nonspecific activators of SIRT1, such as resveratrol, in ADPKD studies is another concern.64,65 NAM is a form of vitamin B3 that in high concentrations can inhibit several NAD-dependent enzymes including sirtuins, CD38, and PARPs.66 In addition, NAM can promote an increase in the tissue NAD levels, including in the kidney, which is protective against ischemic injury in the kidney.67 SIRT1 activity is regulated not only by its expression, but also by the availability of its substrate NAD.68 Interestingly, it has been shown in at least one study that NAD+ levels are much lower in animal models of ADPKD and that expression of the rate-limiting enzyme Nampt is significantly decreased in ADPKD patients and animal models.69 Of interest is whether or not the increased expression of SIRT1 is a response to the decreased availability of NAD or are the effects of vitamin B3 (nicotinamide) mediated by SIRT1 inhibition or by tissues “NAD” boosting. Thus, the use of nicotinamide as a specific SIRT1 inhibitor is questionable and several aspects of the role of NAD metabolism and sirtuins require exploration in ADPKD.
Roles of Melatonin in Maintaining Mitochondrial Welfare
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Feres José Mocayar Marón, Emiliano Diez, Russel J. Reiter, Walter Manucha
The kidney intracellular protection was associated with an elevated number of mitochondria and upregulation of the prosurvival genes such as nicotinamide phosphoribosyltransferase (Nampt) and sirtuin 3 (Sirt3)121. Sirt3 is a member of the family that is localized mostly to the mitochondria and protects against inflammation and oxidative stress-related diseases, including hypertension. Melatonin elevated Sirt3 stimulated SOD activity and suppressed mitochondrial oxidative stress through AMPK122 (Figure 2). Melatonin’s high concentrations and multiple actions as an anti-inflammatory/antioxidant provide substantial protection to mitochondria which are exposed to injury22.
Thermal lesions of the SCN do not abolish all gene expression rhythms in rat white adipose tissue, NAMPT remains rhythmic
Published in Chronobiology International, 2021
Rianne Van Der Spek, Ewout Foppen, Eric Fliers, Susanne La Fleur, Andries Kalsbeek
NAMPT is, indeed, regulated by several more factors involved in cellular energy metabolism. Firstly, AMPK is a key sensor of ATP resources in the cell, and is essential for rhythmicity of NAMPT in WAT. Furthermore, the ratio NAD+/NADH determines the production of reactive oxygen species (ROS), and oxidative stress increases NAMPT release (Lin et al. 2015; Lu et al. 2019). Consequently, NAMPT inhibition induces susceptibility to oxidative stress (Hong et al. 2016; Xu et al. 2017). Anti-oxidant proteins that eliminate ROS, such as peroxiredoxins, may generate rhythmicity in absence of the TTFL (Bass and Takahashi 2011; Edgar et al. 2012; Neill et al. 2011), and may even couple the light signal to the molecular clock (Bodvard et al. 2017). Surprisingly, sWAT contains light sensitive melanopsin channels (Nayak et al. 2020; Ondrusova et al. 2017), raising the suggestion that light could, indeed, reach sWAT. Therefore, the direct effects of light on cellular metabolism pathways could provide an explanation for the remaining rhythmicity in NAMPT, suggesting it is rhythmicity in NAMPT that keeps the molecular clock ticking. On the other hand, this mechanism would not explain the retained rhythmicity in eWAT.
Preclinical assessment of the ADME, efficacy and drug-drug interaction potential of a novel NAMPT inhibitor
Published in Xenobiotica, 2019
Bianca M. Liederer, Jonathan Cheong, Kang-Jye Chou, Peter S. Dragovich, Hoa Le, Xiaorong Liang, Justin Ly, Sophie Mukadam, Jason Oeh, Deepak Sampath, Leslie Wang, Susan Wong
Nicotinamide phosphoribosyltransferase (NAMPT) is a promising target for the identification of new cancer therapies (Bi & Che, 2010; Garten et al., 2009; Sampath et al., 2015; Zhang et al., 2011c). This is the rate-limiting enzyme in the mammalian salvage pathway that catalyzes the conversion of nicotinamide to nicotinamide adenine dinucleotide (NAD) (Burgos, 2011; Tan et al., 2013). NAD is an important cofactor for enzymes involved in numerous fundamental processes that are essential in all living cells, such as cell cycle progression and apoptosis (Chiarugi et al., 2012; Khan et al., 2007). The inhibition of NAMPT leads to the depletion of cellular NAD levels followed by ATP depletion and eventually cell death (Olesen et al., 2010; Tan et al., 2013). Cancer cells are highly susceptible to NAMPT inhibition since they consume NAD and ATP at greater rates than do normal cells (Khan et al., 2007; Vander Heiden, 2011). NAMPT is overexpressed in several tumor cell lines including colon, gastric, ovarian and prostate, and its expression appears to be associated with tumor cell survival and stress response (Bi et al., 2011; Shackelford et al., 2010; Wang et al., 2011).
Rho GTPase effectors and NAD metabolism in cancer immune suppression
Published in Expert Opinion on Therapeutic Targets, 2018
Mahmoud Chaker, Audrey Minden, Suzie Chen, Robert H Weiss, Eduardo N. Chini, Amit Mahipal, Asfar S. Azmi
Many tumor cell types are recognized to have higher expression of NAMPT and this increase has been linked to immune suppression. Often considered as a chemokine, extracellular NAMPT has been shown to regulate signaling in inflammatory cells, such as human monocytes, mouse peritoneal macrophages, and bone marrow-derived macrophages [57,58]. Among the earlier studies, in non-cancer models, NAMPT was shown to link NAD metabolism to inflammatory cytokine secretion by leukocytes [59]. These findings led to the hypothesis that NAMPT inhibition may have therapeutic efficacy in immune-mediated inflammatory disorders. Stimulation of resting monocytes isolated from chronic lymphocytic leukemia (CLL) with NAMPT polarizes them toward tumor-supporting M2 macrophages [60]. Moreover, NAMPT increases expression of immunosuppressive (IL-10) and tumor promoting (IL-6 and IL-8) cytokines. These data suggest an immunosuppressive role of NAMPT in cancer-related inflammation. The enzyme activity independent immune suppression of NAMPT has also been described. In CLL patients with intra- and extracellular plasma over-expression of NAMPT promoted the differentiation of resting monocytes causing their polarizing toward tumor-supporting M2 macrophages [60]. These differentiated monocytes have elevated expression of CD163, CD206, and IDO and secrete immunosuppressive (IL-10, C-C chemokine ligand 18) and tumor-promoting (IL-6, IL-8) cytokines.